Substituted phenylpyrrolecarboxamides with therapeutic activity in hiv

ABSTRACT

Substituted phenylpyrrolecarboxamide compounds such as those represented by Formula A can be used in the treatment of HIV infection and related conditions.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant/ContractNumber 1R01AI104416-01A1 awarded by the National Institutes of Health.The government has certain rights in the invention

BACKGROUND

Human immunodeficiency virus (HIV) is known to cause AIDS. Humanimmunodeficiency virus type 1 (HIV-1) cell entry process is thought tostart when its surface envelope glycoproteins gp120 bind to the hostcell primary receptor CD4. The binding triggers conformational changesin gp120 that facilitate its binding to the host cell coreceptor(secondary) CCR5 or CXCR4. There is no drug available yet that targetsHIV-1 gp120.

Phe43 cavity of HIV-1 gp120 may be a target for developing entryinhibitors for AIDS therapy and prophylaxis.

SUMMARY

Disclosed herein are anti-HIV compounds.

Some embodiments include a pharmaceutical composition, such as anantiviral composition, comprising a compound represented by thefollowing formula:

wherein Ph is optionally substituted phenyl; Py is optionallysubstituted pyrrolyl; or Ph-Py is optionally substituted indolyl; R¹ isH or C₁₋₆ hydrocarbyl; A is H, optionally substituted imidazolyl,optionally substituted thiazolyl, optionally substituted pyrrolyl,morpholine-4-carbonyl, ((2-(methylsulfonamido)ethyl)carbamoyl),optionally substituted piperazin-1-ylcarbamoyl, or optionallysubstituted morpholinocarbamoyl, or (2-hydroxyethyl)carbamoyl); and B isoptionally substituted aminomethyl, optionally substituted amino(C₁_₃alkyl), acetaminomethyl, piperidinyl, optionally substituted guanidino,optionally substituted guanidino(C₁₋₃ alkyl) (such as optionallysubstituted guanidinomethyl, optionally substituted guanidinoethyl, oroptionally substituted guanidinopropyl), optionally substituted phenyl,optionally substituted furanyl, optionally substituted triazolyl,optionally substituted pyrazolyl, or optionally substitutedphenylmethyl; or

is optionally substituted pyrimidinyl.

Some embodiments include a method of inhibiting HIV comprisingadministering a compound described herein to a human being infected withHIV virus.

Some embodiments include a method of treating HIV infection comprisingadministering a compound described herein to a human being infected withHIV virus.

DETAILED DESCRIPTION

Disclosed herein are compounds useful for treating or preventing HIVinfection, and methods of using those compounds. Some of the compoundsdescribed herein may target and inhibit gp120 from binding to the hostcell receptor, CD4.

Unless otherwise indicated, when a compound or chemical structuralfeature such as aryl is referred to as being “optionally substituted,”it includes a feature that has no substituents (i.e. unsubstituted), ora feature that is “substituted,” meaning that the feature has one ormore substituents. The term “substituent” has the broadest meaning knownto one of ordinary skill in the art, and includes a moiety that replacesone or more hydrogen atoms in a parent compound or structural feature.The term “replaces” is merely used herein for convenience, and does notrequire that the compound be formed by replacing one atom with another.In some embodiments, a substituent may be any ordinary organic moietyknown in the art, which may have a molecular weight (e.g. the sum of theatomic masses of the atoms of the substituent) of 15 Da to 50 Da, 15 Dato 100 Da, 15 Da to 150 Da, 15 Da to 200 Da, 15 Da to 300 Da, or 15 Dato 500 Da. In some embodiments, a substituent comprises, or consists of:0-30, 0-20, 0-10, or 0-5 carbon atoms; 0-62, 0-41, 0-21, or 0-11hydrogen atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein eachheteroatom may independently be: N, O, P, S, Si, F, Cl, Br, or I;provided that the substituent includes one C, N, O, P, S, Si, F, Cl, Br,or I atom.

Examples of substituents include, but are not limited to, hydrocarbyl,such as alkyl, alkenyl, alkynyl; heteroalkyl, including any moietywherein one or more heteroatoms replaces one or more carbon atoms of analkyl moiety, and some accompanying hydrogen atoms (e.g. N replaces CH,O replaces CH₂, Cl replaces CH₃, etc.), such as alkoxy, alkylthio,haloalkyl, haloalkoxy, amino, etc.; heteroalkenyl, including any moietywherein one or more heteroatoms replaces one or more carbon atoms of analkenyl moiety, and some accompanying hydrogen atoms, such as acyl,acyloxy, thiocarbonyl, alkylcarboxylate, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, isocyanato,isothiocyanato, etc; heteroalkynyl, including any moiety wherein one ormore heteroatoms replaces one or more carbon atoms of an alkynyl moiety,and some accompanying hydrogen atoms, such as cyano, thiocyanato,cyanato, etc.; aryl; heteroaryl; hydroxy; aryloxy; thiol; halo;S-sulfonamido; N-sulfonamido; nitro; silyl; sulfonyl;trihalomethanesulfonyl; trihalomethanesulfonamido; etc.

For convenience, the term “molecular weight” is used with respect to amoiety or part of a molecule to indicate the sum of the atomic masses ofthe atoms in the moiety or part of a molecule, even though it may not bea complete molecule. If a substituent is anionic or cationic, only thecovalently bonded atoms are counted in the molecular weight. Althoughcounter-ions can be present, they are not included in the determinationof molecular weight. Thus, —CO₂ ⁻Na⁺ would be considered have amolecular weight of about 44 Da and not about 67 Da.

The structures associated with some of the chemical names referred toherein are depicted below. These structures may be unsubstituted, asshown below, or a substituent may independently be in any positionnormally occupied by a hydrogen atom when the structure isunsubstituted. Unless a point of attachment is indicated by

attachment may occur at any position normally occupied by a hydrogenatom.

As used herein, the term “alkyl” has the broadest meaning generallyunderstood in the art, and may include a moiety composed of carbon andhydrogen containing no double or triple bonds. Alkyl may be linearalkyl, branched alkyl, cycloalkyl, or a combination thereof, and in someembodiments, may contain from one to thirty-five carbon atoms. In someembodiments, alkyl may include C₁₋₁₀ linear alkyl, such as methyl(—CH₃), ethyl (—CH₂CH₃), n-propyl (—CH₂CH₂CH₃), n-butyl (—CH₂CH₂CH₂CH₃),n-pentyl (—CH₂CH₂CH₂CH₂CH₃), n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), etc.; C₃₋₁₀branched alkyl, such as C₃H₇ (e.g. iso-propyl), C₄H₉ (e.g. branchedbutyl isomers), C₅H₁₁ (e.g. branched pentyl isomers), C₆H₁₃ (e.g.branched hexyl isomers), C₇H₁₅ (e.g. branched heptyl isomers), etc.;C₃₋₁₀ cycloalkyl, such as C₃H₅ (e.g. cyclopropyl), C₄H₇ (e.g. cyclobutylisomers such as cyclobutyl, methylcyclopropyl, etc.), C₅H₉ (e.g.cyclopentyl isomers such as cyclopentyl, methylcyclobutyl,dimethylcyclopropyl, etc.) C₆H₁₁ (e.g. cyclohexyl isomers), C₇H₁₃ (e.g.cycloheptyl isomers), and the like.

As used herein the term “aryl” has the broadest meaning generallyunderstood in the art, and includes a ring or a ring system having atleast one aromatic ring, such as phenyl, naphthyl, etc.

The term “heteroaryl” also has the meaning understood by a person ofordinary skill in the art, and in some embodiments, may refer to an“aryl” that has one or more heteroatoms in the ring or ring system.Examples of “heteroaryl” may include, but are not limited to, pyridinyl,furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, indolyl, quinolinyl,benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl,benzoimidazolyl, etc.

As used herein, the term “hydrocarbyl” has the broadest meaninggenerally understood in the art, and may include a moiety composed ofcarbon and hydrogen. Some examples may include alkyl, alkenyl, alkynyl,aryl, etc., and combinations thereof, and may be linear, branched,cyclic, or a combination thereof. Hydrocarbyl may be bonded to any othernumber of moieties (e.g. be bonded to 1 other group, such as —CH₃,—CH═CH₂, etc.; 2 other groups, such as -phenyl-, —C≡C—, etc.; or anynumber of other groups) that the structure may bear, and in someembodiments, may contain from one to thirty-five carbon atoms. Examplesof hydrocarbyl groups include but are not limited to C₁ alkyl, C₂ alkyl,C₂ alkenyl, C₂ alkynyl, C₃ alkyl, C₃ alkenyl, C₃ alkynyl, C₄ alkyl, C₄alkenyl, C₄ alkynyl, C₅ alkyl, C₅ alkenyl, C₅ alkynyl, C₆ alkyl, C₆alkenyl, C₆ alkynyl, phenyl, etc.

Unless otherwise indicated, any reference to a compound or anystructural feature herein by structure, name, or any other means,includes pharmaceutically acceptable salts, such as sodium, potassium,and ammonium salts, as well as pharmaceutically acceptable salts foundin Remington's Pharmaceutical Sciences, 17^(th) ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418 and Journal of PharmaceuticalScience, 66, 2 (1977), each of which is incorporated herein by referencein its entirety; prodrugs, such as ester prodrugs; alternate solidforms, such as polymorphs, solvates, hydrates, etc.; tautomers; or anyother chemical species that may rapidly convert to a compound describedherein under conditions in which the compounds are used as describedherein.

With respect to any relevant formula or structural depiction herein,such as Formula A, Ph is optionally substituted phenyl. Ph may have 0,1, 2, 3, or 4 substituents. Any substituent may be included on Ph. Insome embodiments, some or all of the substituents on the ring or ringsystem may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms,wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I(provided that there is at least one non-hydrogen atom); and/or amolecular weight of 15 Da to 500 Da. For example, the substituents maybe C₁₋₁₀ optionally substituted alkyl, such as CH₃, C₂H₅, CO₃H₇, cyclicC₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc.,which may be optionally substituted; C₁₋₁₀ optionally substitutedalkoxy, such as optionally substituted methoxy, optionally substitutedethoxy, etc.; halo, such as F, Cl, Br, I; OH; CN; NO₂; C₁₋₆ fluoroalkyl,such as CF₃, CF₂H, C₂F₅, etc.; a C₁₋₁₀ ester such as —OCOCH₃, —CO₂CH₃,—OCOC₂H₅, —CO₂₂H₅, —OCO-phenyl, —CO₂-phenyl, etc.; a C₁₋₁₀ ketone suchas —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or a C₁₋₁₀ amine such asNH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc.

In some embodiments, Ph may be:

With respect to any relevant formula or structural depiction herein,such as Formula A, Py is optionally substituted pyrrolyl, which may have0, 1, 2, or 3 substituents. Py may have any suitable substituent. Insome embodiments, some or all of the substituents of Py may have: from 0to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatomis independently: O, N, S, F, Cl, Br, or I (provided that there is atleast one non-hydrogen atom); and/or a molecular weight of 15 Da to 500Da. For example, the substituents may be C₁₋₁₀ optionally substitutedalkyl, such as CH₃, C₂H₅, C₃H₇, cyclic C₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁,cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc., which may be optionallysubstituted; C₁₋₁₀ optionally substituted alkoxy, such as optionallysubstituted methoxy, optionally substituted ethoxy, etc.; halo, such asF, Cl, Br, I; OH; CN; NO₂; C₁₋₆ fluoroalkyl, such as CF₃, CF₂H, C₂F₅,etc.; a C₁₋₁₀ ester such as —OCOCH₃, —CO₂CH₃, —OCOC₂H₅, —CO₂C₂H₅,—OCO-phenyl, —CO₂-phenyl, etc.; a C₁₋₁₀ ketone such as —COCH₃, —COC₂H₅,—COC₃H₇, —CO-phenyl, etc.; or a C₁₋₁₀ amine such as NH₂, NH(CH₃),N(CH₃)₂, N(CH₃)C₂H₅, etc.

In some embodiments, Py may be:

With respect to any relevant formula or structural depiction herein,such as Formula A, R¹ can be H; or C₁₋₆ hydrocarbyl, such as alkyl (e.g.CH₃, C₂H₅, C₃H₇, cyclic C₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉,C₆H₁₃, cyclic C₆H₁₁), alkenyl, (e.g. C₂H₃, C₃H₅, etc.) alkynyl, (e.g.C₂H, C₂H₃, etc.), phenyl, etc.

With respect to any relevant formula or structural depiction herein,such as Formula A, A can be H, optionally substituted imidazolyl,optionally substituted thiazolyl, optionally substituted pyrrolyl,morpholine-4-carbonyl, ((2-(methylsulfonamido)ethyl)carbamoyl),optionally substituted piperazin-1-ylcarbamoyl, optionally substitutedmorpholinocarbamoyl, and/or (2-hydroxyethyl)carbamoyl. A may have anysuitable substituent. In some embodiments, some or all of thesubstituents of A may have: from 0 to 10 carbon atoms and from 0 to 10heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl,Br, or I (provided that there is at least one non-hydrogen atom); and/ora molecular weight of 15 Da to 500 Da. For example, the substituents maybe C₁₋₁₀ optionally substituted alkyl, such as CH₃, C₂H₅, C₃H₇, cyclicC₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc.,which may be optionally substituted; C₁₋₁₀ optionally substitutedalkoxy, such as optionally substituted methoxy, optionally substitutedethoxy, etc.; halo, such as F, Cl, Br, I; OH; CN; NO₂; C₁₋₆ fluoroalkyl,such as CF₃, CF₂H, C₂F₅, etc.; a C₁₋₁₀ ester such as —OCOCH₃, —CO₂CH₃,—OCOC₂H₅, —CO₂₂H₅, —OCO-phenyl, —CO₂-phenyl, etc.; a C₁₋₁₀ ketone suchas —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or a C₁₋₁₀ amine such asNH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc.

With respect to any relevant formula or structural depiction herein,such as Formula A, B can be optionally substituted aminomethyl;optionally substituted guanidino; optionally substituted guanidino(C₁₋₃alkyl), such as optionally substituted guanidinomethyl, optionallysubstituted guanidinoethyl, optionally substituted guanidinopropyl;optionally substituted phenyl; optionally substituted furanyl;optionally substituted triazolyl; optionally substituted pyrazolyl;and/or optionally substituted phenylmethyl. B may have any suitablesubstituent. In some embodiments, some or all of the substituents of Bmay have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms,wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I(provided that there is at least one non-hydrogen atom); and/or amolecular weight of 15 Da to 500 Da. For example, the substituents maybe C₁₋₁₀ optionally substituted alkyl, such as CH₃, C₂H₅, CO₃H₇, cyclicC₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc.,which may be optionally substituted; C₁-10 optionally substitutedalkoxy, such as optionally substituted methoxy, optionally substitutedethoxy, etc.; halo, such as F, Cl, Br, I; OH; CN; NO₂; C₁₋₆ fluoroalkyl,such as CF₃, CF₂H, C₂F₅, etc.; a C₁₋₁₀ ester such as —OCOCH₃, —CO₂CH₃,—OCOC₂H₅, —CO₂₂H₅, —OCO-phenyl, —CO₂-phenyl, etc.; a C₁₋₁₀ ketone suchas —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or a C₁₋₁₀ amine such asNH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc.

If stereochemistry is not indicated, such as in Formulas 1-14 andFormula A, a name or structural depiction includes any stereoisomer orany mixture of stereoisomers.

In some embodiments, Formula A may be further described by any of thefollowing Formulas 1-14.

With respect to any relevant structural representation, such as Formulas1 and 2, in some embodiments, Y is C₁₋₃ hydrocarbyl, including C₁₋₃alkylene, such as —CH₂—, —C₂H₄—, —C₃H₆—, or C₂₋₃ alkenyl or alkynyl. Insome embodiments Y is a bond.

With respect to any relevant structural representation, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R¹⁵, R^(15a), R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, and R²⁸, may independently be H, a halide,or a substituent having a molecular weight of 15 Da to 300 Da or 15 Dato 150 Da and consisting of 2 to 5 chemical elements, wherein thechemical elements are independently C, H, O, N, S, P, F, Cl, Br, or I.In some embodiments, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, and R²⁸ areindependently R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R¹⁵, R^(15a),R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, and R²⁸ areindependently H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl,ethyl, propyl isomers (e.g. n-propyl and isopropyl), cyclopropyl, butylisomers, cyclobutyl isomers (e.g. cyclobutyl and methylcyclopropyl),pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers,etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl,—O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomersof —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of—O-cyclohexyl, etc.

With respect to any relevant structural representation, each R^(A) mayindependently be H, or C₁₋₁₂ alkyl, including: linear or branched alkylhaving a formula C_(a)H_((2a)+1), or cycloalkyl having a formulaC_(a)H_((2a)−1), wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12,such as linear or branched alkyl of a formula: CH₃, C₂H₅, CO₃H₇, C₄H₉,C₅H₁₁, C₆H₁₃, C₇H₁₅, C₉H₁₇, C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl of aformula: C₃H₅, C₄H₇, C₅H₉, C₆H₁₁, C₇H₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. Insome embodiments, R^(A) may be H or C₁₋₆ alkyl. In some embodiments,R^(A) may be H or C₁₋₃ alkyl. In some embodiments, R^(A) may be H orCH₃. In some embodiments, R^(A) may be H.

With respect to any relevant structural representation, each R^(B) mayindependently be H, or C₁₋₁₂ alkyl, including: linear or branched alkylhaving a formula C_(a)H_((2a)+1); or cycloalkyl having a formulaC_(a)H_((2a)−1), wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12,such as linear or branched alkyl of a formula: CH₃, C₂H₅, CO₃H₇, C₄H₉,C₅H₁₁, C₆H₁₃, C₈H₁₇, C₇H₁₅, C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl of aformula: C₃H₅, C₄H₇, C₅H₉, C₆H₁₁, C₇H₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. Insome embodiments, R^(B) may be H or C₁₋₃ alkyl. In some embodiments,R^(B) may be H or CH₃. In some embodiments, R^(B) may be H.

With respect to Formulas 1-14, in some embodiments, R⁴ is H, F, Cl, NH₂,CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R⁴ is H.Additionally, for any embodiments recited in this paragraph, R⁵, R⁶, R⁷,and R⁸ can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), orCONR^(A)R^(B); or H, F, Cl, ON, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆alkoxy.

With respect to Formulas 1-14, in some embodiments, R⁵ is H, F, Cl, NH₂,CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R⁵ is H. Insome embodiments, R⁵ is F. Additionally, for any embodiments recited inthis paragraph, R⁴, R⁶, R⁷, and R⁸ can independently be: R^(A), F, Cl,ON, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), or CONR^(A)R^(B); or H, F, Cl, ON, CF₃, OH, NH₂, C₁₋₆alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R⁶ is H, F, Cl, NH₂,CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R⁶ is H. Insome embodiments, R⁶ is Cl. In some embodiments, R⁶ is CH₃.Additionally, for any embodiments recited in this paragraph, R⁴, R⁵, R⁷,and R⁸ can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), orCONR^(A)R^(B); or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆alkoxy.

With respect to Formulas 1-14, in some embodiments, R⁷ is H, F, Cl, NH₂,CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R⁷ is H. Insome embodiments, R⁷ is F. Additionally, for any embodiments recited inthis paragraph, R⁴, R⁵, R⁶, and R⁸ can independently be: R^(A), F, Cl,CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), or CONR^(A)R^(B); Or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R⁸ is H, F, Cl, NH₂,CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R⁸ is H.Additionally, for any embodiments recited in this paragraph, R⁴, R⁵, R⁶,and R⁷ can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), orCONR^(A)R^(B); or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆alkoxy.

With respect to Formulas 1-14, in some embodiments, R⁴ and R⁵ are H. Insome embodiments, R⁵ and R⁶ are H. In some embodiments, R⁶ and R⁷ are H.In some embodiments, R⁷ and R⁸ are H. In some embodiments, R⁴, R⁵, R⁶,R⁷, and R⁸ are H.

With respect to Formulas 1-14, in some embodiments, R⁹ is H, F, Cl, NH₂,CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R⁹ is H.Additionally, for any embodiments recited in this paragraph, R¹⁰, andR¹¹ can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), orCONR^(A)R^(B); or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆alkoxy.

With respect to Formulas 1-14, in some embodiments, R¹⁰ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R¹⁰ is H.Additionally, for any embodiments recited in this paragraph, R⁹, and R¹¹can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B),COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), or CONR^(A)R^(B); or H, F,Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R¹¹ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R¹¹ is H.Additionally, for any embodiments recited in this paragraph, R⁹, and R¹⁰can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B),COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), or CONR^(A)R^(B); or H, F,Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R¹³ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R¹³ is H.In some embodiments, R¹³ is —CH₂OH. Additionally, for any embodimentsrecited in this paragraph, R¹⁴ and R²² can independently be: R^(A), F,Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), or CONR^(A)R^(B); Or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R¹⁴ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R¹⁴ is H.In some embodiments, R¹⁴ is CH₃. Additionally, for any embodimentsrecited in this paragraph, R¹³ and R²² can independently be: R^(A), F,Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), or CONR^(A)R^(B); Or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R¹⁵ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R¹⁵ is H.In some embodiments, R¹⁵ and R^(15a) may together form a ring, such as,but not limited to piperidinyl. In some embodiments, R¹⁵ is CH₃. In someembodiments, R¹⁵ is acetyl. In some embodiments, R¹⁵ is carbamimidoyl.Additionally, for any embodiments recited in this paragraph, R^(15a) andR¹⁶ can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), orCONR^(A)R^(B); or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆alkoxy.

With respect to Formulas 1-14, in some embodiments, R^(15a) is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R^(15a) isH. In some embodiments, R¹⁵ and R^(15a) may together form a ring, suchas, but not limited to piperidinyl. In some embodiments, R^(15a) is CH₃.In some embodiments, R¹⁵ is acetyl. In some embodiments R^(15a) iscarbamimidoyl. Additionally, for any embodiments recited in thisparagraph, R¹⁵ and R¹⁶ can independently be: R^(A), F, Cl, CN, OR^(A),CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), orCONR^(A)R^(B); or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆alkoxy.

With respect to Formulas 1-14, in some embodiments, R¹⁶ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R¹⁶ is H.Additionally, for any embodiments recited in this paragraph, R¹⁵ and,where applicable, R²³ can independently be: R^(A), F, Cl, CN, OR^(A),CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), orCONR^(A)R^(B); or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆alkoxy.

With respect to Formulas 1-14, in some embodiments, R¹⁷ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R¹⁷ is H.In some embodiments, R¹⁷ is methoxy. Additionally, for any embodimentsrecited in this paragraph, R¹⁸, R¹⁹, R²⁰, and R²¹ can independently be:R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A),OCOR^(A), NR^(A)COR^(B), or CONR^(A)R^(B); or H, F, Cl, CN, CF₃, OH,NH₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R¹⁸ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R¹⁸ is H.In some embodiments, R¹⁸ is guanidino. In some embodiments, R¹⁸ is(diethylamino)methyl. Additionally, for any embodiments recited in thisparagraph, R¹⁷, R¹⁹, R²⁰, and R²¹ can independently be: R^(A), F, Cl,ON, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), or CONR^(A)R^(B); Or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R¹⁹ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R¹⁹ is H.Additionally, for any embodiments recited in this paragraph, R¹⁷, R¹⁸,R²⁰, and R²¹ can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), orCONR^(A)R^(B); or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆alkoxy.

With respect to Formulas 1-14, in some embodiments, R²⁰ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R²⁰ is H.In some embodiments, R²⁰ is methylamino. In some embodiments, R²⁰ is(diethylamino)methyl. In some embodiments, R²⁰ is SO₂NH₂. Additionally,for any embodiments recited in this paragraph, R¹⁷, R¹⁸, R¹⁹, and R²¹can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B),COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), or CONR^(A)R^(B); or H, F,Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R²¹ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R²¹ is H.In some embodiments, R²¹ is methoxy. Additionally, for any embodimentsrecited in this paragraph, R¹⁷, R¹⁸, R¹⁹, and R²⁰ can independently be:R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A),OCOR^(A), NR^(A)COR^(B), or CONR^(A)R^(B); or H, F, Cl, CN, CF₃, OH,NH₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R²² is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R²² is H.Additionally, for any embodiments recited in this paragraph, R¹³ and R¹⁴can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B),COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), or CONR^(A)R^(B); or H, F,Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R²³ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R²³ is H.Additionally, for any embodiments recited in this paragraph, R¹⁶ canindependently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B),COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), or CONR^(A)R^(B); or H, F,Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R²⁴ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R²⁴ is H.Additionally, for any embodiments recited in this paragraph, R²⁵ canindependently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B),COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), or CONR^(A)R^(B); or H, F,Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R²⁵ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R²⁵ is H.Additionally, for any embodiments recited in this paragraph, R²⁴ canindependently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B),COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), or CONR^(A)R^(B); or H, F,Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R²⁶ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R²⁶ is H.In some embodiments, R²⁶ is NH₂. Additionally, for any embodimentsrecited in this paragraph, R²⁷ and R²⁸ can independently be: R^(A), F,Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), or CONR^(A)R^(B); or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R²⁷ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R²⁷ is H.Additionally, for any embodiments recited in this paragraph, R²⁶ and R²⁸can independently be: R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B),COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), or CONR^(A)R^(B); or H, F,Cl, CN, CF₃, OH, NH₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

With respect to Formulas 1-14, in some embodiments, R²⁸ is H, F, Cl,NH₂, CH₃, SO₂NH₂, OCH₃, CH₂OH, N(C₂H₅)₂. In some embodiments, R²⁸ is H.In some embodiments, R²⁸ is CH₃. Additionally, for any embodimentsrecited in this paragraph, R²⁶ and R²⁷ can independently be: R^(A), F,Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), or CONR^(A)R^(B); Or H, F, Cl, CN, CF₃, OH, NH₂, C₁₋₆alkyl, or C₁₋₆ alkoxy.

In some embodiments, a compound of Formula 1 can be:

In some embodiments, a compound of Formula 2 can be:

In some embodiments, a compound of Formula 3 can be:

In some embodiments, a compound of Formula 4 can be:

In some embodiments, a compound of Formula 5 can be:

In some embodiments, a compound of Formula 6 can be:

In some embodiments, a compound of Formula 7 can be:

In some embodiments, a compound of Formula 8 can be:

In some embodiments, a compound of Formula 9 can be:

In some embodiments, a compound of Formula 10 can be:

In some embodiments, a compound of Formula 11 can be:

In some embodiments, a compound of Formula 12 can be:

In some embodiments, a compound of Formula 13 can be:

In some embodiments, a compound of Formula 14 can be:

The compounds described herein, such as compounds of Formulas A and 1-14(referred to hereafter as “subject compounds” or “subject compound”) maybe used as inhibitors of human immunodeficiency virus (HIV) and/or fortreating associated diseases, disorders, and conditions. Apharmaceutical composition comprising at least one subject compound maybe administered to individuals suffering from or susceptible to HIV-1infection.

Appropriate excipients for use in a pharmaceutical compositioncomprising a subject compound (referred to hereafter as “subjectcompositions” or “subject composition”) may include, for example, one ormore carriers, binders, fillers, vehicles, disintegrants, surfactants,dispersion or suspension aids, thickening or emulsifying agents,isotonic agents, preservatives, lubricants, and the like or combinationsthereof, as suited to a particular dosage from desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. This document is incorporatedherein by reference in its entirety.

A subject composition may be formulated for any desirable route ofdelivery including, but not limited to, parenteral, intravenous,intradermal, subcutaneous, oral, inhalative, transdermal, topical,transmucosal, rectal, interacisternal, intravaginal, intraperitoneal,buccal, and intraocular.

In certain aspects, parenteral, intradermal or subcutaneous formulationsmay be sterile injectable aqueous or oleaginous suspensions. Acceptablevehicles, solutions, suspensions and solvents may include, but are notlimited to, water or other sterile diluent; saline; Ringer's solution;sodium chloride; fixed oils such as mono- or diglycerides; fatty acidssuch as oleic acid; polyethylene glycols; glycerine; propylene glycol orother synthetic solvents; antibacterial agents such as benzyl alcohol;antioxidants such as ascorbic acid; chelating agents such asethylenediaminetetraacetic acid; buffers such as acetates, citrates orphosphates; and agents for the adjustment of tonicity such as sodiumchloride or dextrose.

Solutions or suspensions used for parenteral, intradermal, orsubcutaneous application may include one or more of the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine; propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfate; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation may be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use may includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersion. For intravenous administration, suitable carriers include,but are not limited to, saline, bacteriostatic water, CREMOPHOR EL(BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The solventor dispersion medium may contain, for example, water, ethanol, polyol(for example, glycerol, propylene glycol, and liquid polyetheyleneglycol, and the like), and suitable mixtures thereof. Proper fluiditycan be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Preventing growth ofmicroorganisms can be achieved by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, ascorbic acid,thimerosal, and the like. The composition may also include isotonicagents such as, for example, sugars; polyalcohols such as manitol;sorbitol; or sodium chloride. Prolonged absorption of injectablecompositions can be enhanced by addition of an agent that delaysabsorption, such as, for example, aluminum monostearate or gelatin.

Oral compositions may include an inert diluent or an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets.Tablets, pills, capsules, troches and the like can contain any of thefollowing ingredients, or compounds of a similar nature: a binder suchas microcrystalline cellulose, gum tragacanth or gelatin; an excipientsuch as starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate; aglidant such as colloidal silicon dioxide; a sweetening agent such assucrose or saccharin; or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring.

In addition to oral or injected administration, systemic administrationmay be by transmucosal or transdermal means. For transmucosal ortransdermal administration, penetrants may be used. Such penetrants aregenerally known in the art, and include, for example, detergents, bilesalts, and fusidic acid derivatives. Transdermal administration mayinclude a bioactive agent and may be formulated into ointments, salves,gels, or creams as generally known in the art. Transmucosaladministration may be accomplished through the use of nasal sprays orsuppositories.

A subject compound may be administered in a therapeutically effectiveamount, according to an appropriate dosing regiment. As understood by askilled artisan, an exact amount required may vary from subject tosubject, depending on a subject's species, age and general condition,the severity of the infection, the particular agent(s) and the mode ofadministration. In some embodiments, about 0.001 mg/kg to about 50mg/kg, of the pharmaceutical composition based on the subject's bodyweight is administered, one or more times a day, to obtain the desiredtherapeutic effect. In other embodiments, about 0.01 mg/kg to about 25mg/kg, of the pharmaceutical composition based on the subject's bodyweight is administered, one or more times a day, to obtain the desiredtherapeutic effect.

A total daily dosage of a subject compound can be determined by theattending physician within the scope of sound medical judgment. Aspecific therapeutically effective dose level for any particular patientor subject will depend upon a variety of factors including the disorderbeing treated and the severity of the disorder; the activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient or subject; thetime of administration, route of administration, and rate of excretionof the specific compound employed; the duration of the treatment; drugsused in combination or coincidental with the specific compound employed;and other factors well known in the medical arts.

In some embodiments, a method of treating HIV infection comprisesadministering a compound of any one of Formulae 1-14, or apharmaceutically acceptable salt thereof, to a human being infected withHIV.

In some embodiments, a method of treating HIV infection comprisesadministering any one of compounds 1-130, or a pharmaceuticallyacceptable salt thereof, to a human being infected with HIV.

In some embodiments, a method of treating HIV infection comprisesadministering compound 15, or a pharmaceutically acceptable saltthereof, to a human being infected with HIV.

In some embodiments, a method of treating HIV infection comprisesadministering compound 17, or a pharmaceutically acceptable saltthereof, to a human being infected with HIV.

In some embodiments, a method of treating HIV infection comprisesadministering compound 39, or a pharmaceutically acceptable saltthereof, to a human being infected with HIV.

In some embodiments, a method of treating HIV infection comprisesadministering compound 41, or a pharmaceutically acceptable saltthereof, to a human being infected with HIV.

In some embodiments, a method of treating HIV infection comprisesadministering compound 99, or a pharmaceutically acceptable saltthereof, to a human being infected with HIV.

In some embodiments, a method of treating HIV infection comprisesadministering compound 120, or a pharmaceutically acceptable saltthereof, to a human being infected with HIV.

Although there are many ways in which Formula A might be prepared,Formula A can be synthesized by a peptide coupling reaction, as follows,which couples Precursor 1 with Intermediate 1 to form Formula A.

In some embodiments, Intermediate 1 is pretreated with tetraphenylboratebefore the peptide coupling reaction is carried out to avoid unintendedcoupling of amino substituents (see U.S. Pat. No. 5,262,567).

Although there are many ways that Intermediate 1 can be prepared,Intermediate 1, having a structure

H₂N pan be prepared as shown in Scheme 1.

Although there are many ways that Intermediate 1 can be prepared,Intermediate 1, having a structure

can be prepared as shown in Scheme 2.

Although there are many ways that Intermediate 1 can be prepared,Intermediate 1, having a structure

can be prepared as shown in Scheme 3.

Although there are many ways that Intermediate 1 can be prepared,Intermediate 1, having a structure

can be prepared as shown in Scheme 4.

EXAMPLES

Single-Cycle Infection Assay in TZM-bl Cells.

The inhibitory activity of test compounds was measured on HIV-1pseudotyped viruses expressing HIV-1HXB-2 ENV or ENV from the panel ofstandard reference subtype A, A/D, A2/D, A/E, A/G, B, C and D.Pseudoviruses were obtained by transfecting HEK 293T cells with amixture of an Env-deleted backbone proviral plasmid pSG3Δenv and an Envexpression vector DNA. Briefly, 100 μl of TZM-bl cells at 1×105 cells/mlwas added to the wells of a 96 well tissue culture plate and cultured at37° C. overnight. 50 μl of a test compound at graded concentrations wasmixed with 50 μl of the HIV-1 pseudovirus at about 100 TCID50. Afterincubation at 37° C. for 30 min, the mixture was added to the cells andincubated at 37° C. for 3 days. Cells were washed 2 times with PBS andlysed with 50 μl of cell culture lysis reagent. 20 μl of lysates weretransferred to a white 96 well plate and mixed with 100 μl of luciferaseassay reagent. The luciferase activity was immediately measured with aTecan infinite M1000 reader and the percent inhibition by the compoundsand IC₅₀ values were calculated using the GraphPad Prism software. (seeTable 1 & 2)

TABLE 1 Antiviral activity of small molecules in single cycle assay,TZM-bl cells infected with HIV-1 pseudovirus pseudotyped with HXB2 Env.Compound TZM-bl Number Structure IC₅₀ (μM) CC₅₀(μM) 1

16.4 ± 1.5  >53 2

>63 >63 3

>36 >36 4

>44 >44 5

>47 >47 6

>37 >37 7

>43 >43 8

>42 >42 9

>40 >40 10

>43 >43 11

~60 ~60 12

14.1 ± 1.3   22 ± 0.4 13

4.3 ± 0.1 14.2 ± 1   14

>50 >50 15

  Diastereoisomeric mixtures 2.5 ± 0.2 ~28 16

  Stereoisomer 1 3.2 ± 0.3 ~30 17

  Stereoisomer 2 2.2 ± 0.2 ~24 18

  Stereoisomer 3 3.0 ± 0.1 ~28 19

  Stereoisomer 4 0.99 ± 0.13 ~24 20

  Diastereoisomer 1   3 ± 0.4 15.2 ± 0.2  21

  Diastereoisomer 2 3.2 ± 0.5 17.4 ± 1.6  22

  Diastereoisomer 1 2.7 ± 0.2 ≥36 23

  Diastereoisomer 2 3.8 ± 0.3 ≥36 24

  Diastereoisomer 1 10.6 ± 0.1  28.8 ± 1   25

  Diastereoisomer 2 6.3 ± 0.3 15.3 ± 0.2  26

  Diastereoisomer 1 7.5 ± 0.2 16.1 ± 0.2  27

  Diastereoisomer 2   8 ± 0.1 15.1 ± 0.2  28

  Diastereoisomer 1 8.9 ± 0.2 17.3 ± 0.1  29

  Diastereoisomer 2 5.9 ± 0.2 15.4 ± 0.3  30

  Diastereoisomer 1 11.2 ± 0.7   17 ± 0.7 31

  Diastereoisomer 1 5.1 ± 0.7 8.2 ± 0.3 32

  Stereoisomeric mixtures 7.6 ± 0.8 13.7 ± 1   33

  Diastereoisomer 1  14 ± 0.1  28 ± 0.5 34

  Diastereoisomer 2  16 ± 0.1  34 ± 0.1 35

  Diastereoisomer 1   9 ± 0.2  25 ± 0.5 36

  Diastereoisomer 2 16.2 ± 0.2  31.5 ± 0.2  37

  Diastereoisomer 1 9.6 ± 0.1  30 ± 0.3 38

  Diastereoisomer 2  17 ± 0.2  34 ± 0.2 39

  Stereoisomer 1 2.1 ± 0.2 ≥34 40

  Stereoisomer 2 6.5 ± 1.6 ~40 41

  Stereoisomer 2 0.59 ± 0.06 ≥33 42

  Stereoisomer 1 0.68 ± 0.03 ≥33 43

  Stereoisomer 1 1.7 ± 0.4 ≥34 44

  Stereoisomer 2 1.1 ± 0.1 ≥34 45

  Stereoisomer 1 >37 >37 46

  Stereoisomer 2 ≥20 >37 47

  Stereoisomer 1 ≥20 >36 48

  Stereoisomer 2 >27 >36 49

  Stereoisomer 1 >28 >37 50

  Stereoisomer 2 >20 >37 51

  Stereoisomer 1 1.4 ± 0.5 ~28 52

  Stereoisomer 2 0.89 ± 0.1  50.5 ± 1.3  53

>36 ≥36 54

  Stereoisomer 1 1.6 ± 0.6 ~20 55

  Stereoisomer 2 2.1 ± 0.9 ~40 56

  Stereoisomer 1 1.6 ± 0.6 ~21 57

  Stereoisomer 2 ~0.6 ~20 58

  Stereoisomer 1 3.3 ± 0.5 ~37 59

  Stereoisomer 2 3.4 ± 0.6 ~22 60

  Stereoisomer 1 ~40 >44 61

  Stereoisomer 2 ~40 >44 62

  Stereoisomer 1  22 ± 3.8 >40 63

  Stereoisomer 2 16.5 ± 3.4  ~30 64

  Stereoisomer 1 ~40 ~40 65

  Stereoisomer 2 6.3 ± 1.8 >40 66

  Stereoisomer 2 >40 >40 67

  Stereoisomer 1 3.6 ± 1   ~29 68

  Stereoisomer 2 7.2 ± 3   ~29 69

  Stereoisomer 1 2.2 ± 0.8 27.2 ± 0.8  70

  Stereoisomer 2 1.1 ± 0.3 26.4 ± 0.7  71

3.3 ± 0.6 19.4 ± 0.9  72

  Stereoisomer 1  11 ± 2.5 36.4 ± 1   73

  Stereoisomer 2 6.6 ± 0.2 37.1 ± 5.7  74

  Stereoisomer 1 4.6 ± 0.2 22 ± 1  75

  Stereoisomer 2 1.5 ± 0.3 21.3 ± 0.6  76

  Stereoisomer 1 14.2 ± 0.7  21.7 ± 1   77

  Stereoisomer 2 10.4 ± 2   40.2 ± 3   78

  Stereoisomer 1 10.4 ± 0.2  36.4 ± 2.6  79

  Stereoisomer 2 1.6 ± 0.4 38.9 ± 2.1  80

  Stereoisomer 1 9.1 ± 1.1 22.3 ± 0.6  81

  Stereoisomer 2 1.5 ± 0.4  22 ± 0.6 82

  Stereoisomer 1 18.6 ± 1.5   23 ± 1.2 83

  Stereoisomer 2 1.7 ± 0.2  23 ± 0.6 84

  Stereoisomer 1 18.2 ± 2.6   47 ± 0.6 85

  Stereoisomer 2 4.2 ± 1.7 43.8 ± 1.6  86

  Stereoisomer 1 4.1 ± 1.5 22.9 ± 0.6  87

  Stereoisomer 2 6.6 ± 2   35 ± 3  88

  Stereoisomer 1 18.7 ± 0.7   41 ± 1.1 89

  Stereoisomer 2   4 ± 0.3 41 ± 1  90

  Stereoisomer 1 1.1 ± 0.8 37.4 ± 0.3  91

  Stereoisomer 1  26 ± 1.4 35.8 ± 0.3  92

  Stereoisomer 2 25.8 ± 1.1  36.7 ± 0.4  93

  Stereoisomer 1 >51 >51 94

  Stereoisomer 2 >51 >51 95

  Stereoisomer 1 34.9 ± 3   >51 96

  Stereoisomer 2 ~51 >51 97

  Stereoisomer 1 2.6 ± 0.1 5.2 ± 0.3 98

  Stereoisomer 2 3.6 ± 0.4 22.2 ± 0.3  99

  Stereoisomer 1 0.60 ± 0.01 38.8 ± 0.8  100

  Stereoisomer 2 0.85 ± 0.06 39.2 ± 0.8  101

  Stereoisomer 1 0.57 ± 0.01 30.8 ± 1.9  102

  Stereoisomer 2 0.77 ± 0.04 31.8 ± 0.4  103

  Stereoisomer 1 0.75 ± 0.2  37.1 ± 0.3  104

  Stereoisomer 2 1.3 ± 0.1  38 ± 1.5 105

  Stereoisomer 1 8.8 ± 0.5 16.7 ± 0.1  106

  Stereoisomer 2 12.4 ± 2.5  22.2 ± 2.5  107

  Stereoisomer 2 4.2 ± 0.3 28.5 ± 3.5  108

  Stereoisomer 1 12.1 ± 0.5  14.6 ± 0.2  109

  Stereoisomer 1 1.4 ± 0.5 22.1 ± 1.8  110

  Stereoisomer 2 1.1 ± 0.2 20.6 ± 1.2  111

  Stereoisomer 1 0.44 ± 0.03  14 ± 0.4 112

  Stereoisomer 2 0.27 ± 0.04 13.9 ± 0.7  113

  Stereoisomer 1 1.1 ± 0.1 17.1 ± 0.6  114

  Stereoisomer 2 0.34 ± 0.02 17.8 ± 0.3  115

  Stereoisomer 1 0.95 ± 0.03 17.3 ± 0.5  116

  Stereoisomer 2  1.4 ± 0.05 17.4 ± 0.4  117

  Stereoisomer 1   1 ± 0.2 27.4 ± 0.8  118

  Stereoisomer 2   2 ± 0.3  21 ± 0.8 119

  Stereoisomer 1 0.48 ± 0.1   18 ± 0.5 120

  Stereoisomer 2 0.64 ± 0.06 31.4 ± 1.1  121

  Stereoisomer 2 3.4 ± 0.7 >51 (30%) 122

  Stereoisomer 1 3.3 ± 0.3 >51 (30%) 123

  Stereoisomer 1 0.56 ± 0.03 14.5 ± 2   124

  Stereoisomer 2 0.46 ± 0.01 16.3 ± 0.6  125

  Stereoisomer 1 0.63 ± 0.03 32.5 ± 0.3  126

  Stereoisomer 2 0.54 ± 0.01 18.1 ± 0.7  127

  Stereoisomer 1 0.42 ± 0.2  13.9 ± 0.7  128

  Stereoisomer 2 0.36 ± 0.04 10.4 ± 0.8  129

  Stereoisomer 1 >74.5 >74.5 130

  Stereoisomer 2 >74.5 >74.5

indicates data missing or illegible when filed

Example 3

Example 4 Cell-to-Cell Fusion

To assess the ability of NBD-compounds to block cell-to-cell fusionmediated by HIV-1 we performed cell fusion assay as previously described3¹⁻³ with some modifications. We used MAGI-CCR5 cells, a HeLa cell cloneexpressing human CD4, both co-receptors CXCR4 and CCR5 andHIV-LTR-β-gal^(2,4) as target cells and HL 2/3 cells, a HeLa-derivedcell line which express HIV-1_(HXB2) Env on the surface and Tat, Gag,Rev and Nef proteins in the cytoplasm and does not produce detectableamounts of mature virions⁵ as effector cells. Following fusion of thetwo cell lines Tat induce the expression of β-gal enzyme. Briefly,following pre-incubation of 1.5×10⁴/well MAGI-CCR5 cells for 1 hr withescalating concentrations of NBD-compounds, 7.5×10³/well HL 2/3 cellswere added to the culture and incubated for 24 h at 37° C. β-galexpression was quantified with the BETA-GLO Assay System (Promega)following the manufacturer's instructions. The percent inhibition andthe IC₅₀ values were calculated using the GraphPad Prism software. (SeeTable 3)

In Vitro Biochemical HIV RT and Integrase Assay

Purified recombinant HIV (pNL4-3) heterodimeric (p66/p51) ReverseTranscriptase (RT) was purchased from a commercially available source.The assay was performed in 96-well filter plate, where RT activity wasdetermined by the incorporation of radiolabeled deoxyribonucleotidesinto the newly synthesized DNA strand. The standard RT reaction mixturecontains in vitro transcribed viral RNA derived from the HIV-1_(NL4-3)5′-LTR region (position 454 to 652) and primer that is complementary tothe primer binding site (PBS, nucleotide residues nucleotides 636 to652), radiolabeled deoxyribonucleotide, dNTPs and reverse transcriptase.Briefly, the reaction was carried out in a volume of 50 μl containing 50mM Tris HCl, pH 7.8, 50 mM KCl, 5 mM MgCl₂, 1 mM DTT, 50 μM each ofdATP, dCTP, dGTP, 50 nM dTTP, 1 μCi of [³H] dTTP (70-90 Ci/mM) and 5 nMtemplate/primer. The reaction was initiated by the addition of 10 nM RT.

Compounds were diluted in 100% DMSO to 40 mM. Each compound was dilutedin the appropriate reaction buffer for the biochemical assay perprotocol. Serially diluted test compounds were added to the reactionfollowed by the addition of RT. The reaction mixture was incubated at37° C. for 1 h, and then quenched by the addition of ice-coldtrichloroacetic acid (TCA) to the final concentration of 10%. The platewas incubated at 4° C. for 1 h to precipitate the synthesized DNA, thenrinsed 3-times with 10% TCA and 1 time with 70% ethanol. After additionof 25 μl scintillation fluid to completely dried wells, radioactivitywas counted by MicroBeta scintillation counter (PerkinElmer). Thereduction of radioactivity represents the potency of compoundinhibition. (See Table 3)

HIV-1 Integrase was performed as per the protocol in the HIV-1 IntegraseAssay Kit from ExpressBio (Thurnmont, Md.). (See Table 3)

Multi-Cycle Infection Assay in MT-2 Cells.

The inhibitory activity of test compounds on infection bylaboratory-adapted HIV-1 strains was determined as previouslydescribed⁶. Briefly, 1×10⁴ MT-2 cells were infected with HIV-1_(IIIB)and other lab-adapted HIV-1 at 100 TCID₅₀ (0.01 MOI) in the presence orabsence of test compounds at graded concentrations overnight. Theculture supernatants were then removed and fresh media were added. Onthe fourth day post-infection, 100 μl of culture supernatants werecollected from each well, mixed with equal volume of 5% Triton X-100 andtested for p24 antigen by “sandwich” ELISA. (See Table 4)

Multi-Cycle Infection Assay in PBMC.

The inhibitory activity of test compounds on infection by primary HIV-1isolates was determined as previously described⁶. PBMCs were isolatedfrom the blood of healthy donors at the New York Blood Center bystandard density gradient centrifugation using Histopaque-1077(Sigma-Aldrich). The cells were cultured at 37° C. for 2 hr.Non-adherent cells were collected and cultured at 5×10⁶ cells/mlRPMI-1640 medium containing 10% FBS, 5 μg/ml PHA, and 100 U/ml IL-2(Sigma-Aldrich), followed by incubation at 37° C. for 3 days. ThePHA-stimulated cells (5×10⁴ cells/well) were infected with lab-adaptedand primary HIV-1 isolates at 500 TCID₅₀ (0.01 MOI) in the absence orpresence of inhibitors at graded concentrations. Culture media werereplaced every 3 days with fresh media. The supernatants were collected7 days post-infection and tested for p24 antigen by ELISA. The percentinhibition of p24 production and IC₅₀ values were calculated by theGraphPad Prism software. (See Table 4)

Determination of Cytotoxicity

MT-2 Cells.

Cytotoxicity of test compounds in MT-2 cells was measured a bycolorimetric method using XTT [(sodium3′-(1-(phenylamino)-carbonyl)-3,4-tetrazolium-bis(4-methoxy-6-nitro)bezenesulfonic acid hydrate)] (PolySciences) as previously described⁷.Briefly, 100 μl of a test compound at graded concentrations was added toan equal volume of cells (1×10⁵ cells/ml) in 96 well plates followed byincubation at 37° C. for 4 days, which ran parallel to theneutralization assay in MT-2. Following the addition of XTT the solubleintracellular formazan was quantitated colorimetrically at 450 nm 4 hlater. The percent of cytotoxicity and the CC₅₀ (the concentration for50% cytotoxicity) values were calculated by the GraphPad Prism software.(See Table 4)

TZM-bl Cells.

The cytotoxicity of test compounds in TZM-bl cells was also measured bythe XTT method described previously⁷. Briefly, 100 μl of a compound atgraded concentrations was added to equal volume of cells (10⁵/ml) inwells of 96 well plates followed by incubation at 37° C. for 3 days andaddition of XTT. The soluble intracellular formazan was quantitatedcolorimetrically at 450 nm 4 h later. The percent of cytotoxicity andthe CC₅₀ values were calculated as above. (See Table 4)

PBMC.

For the PBMC toxicity assay we used 5×10⁵ cells/ml and the cytotoxicityof the compounds was measured after 7 days of incubation as previouslyreported⁸. Following the addition of XTT the soluble intracellularformazan was quantitated colorimetrically at 450 nm 4 h later. Thepercent of cytotoxicity and the CC₅₀ values were calculated as above.(See Table 4)

TABLE 2 Inhibitory activity of Compounds 17, 39, 41, 99 and 120 againsta panel of HIV-1 ENV-pseudoviruses IC₅₀ (μM) ± S.D.^(#) HIV-1 CompoundCompound Compound Compound Compound Subtype NIH # ENVs 17 39 41 99 120 A11887 Q259env.w6 1.6 ± 0.1  1.3 ± 0.02 0.74 ± 0.06  0.5 ± 0.08 0.36 ±0.04 11888 QB726.70M.ENV.C4 1.3 ± 0.3 0.8 ± 0.3 0.87 ± 0.2  0.51 ± 0.020.51 ± 0.03 11890 QF495.23M.ENV.A1 1.3 ± 0.4 1.2 ± 0.3 0.62 ± 0.04 0.79± 0.15  0.8 ± 0.03 11891 QF495.23M.ENV.A3 0.88 ± 0.4   0.5 ± 0.08 0.31 ±0.01  0.6 ± 0.01 0.44 ± 0.07 11892 QF495.23M.ENV.B2 0.6 ± 0.4 0.74 ±0.1  0.52 ± 0.07 0.27 ± 0.03 0.68 ± 0.06 BG505-T332N  1 ± 0.1 0.78 ±0.2  0.33 ± 0.04 0.99 ± 0.1  0.41 ± 0.02 KNH1144 2.1 ± 0.4 0.67 ± 0.020.43 ± 0.2  1.1 ± 0.2 0.46 ± 0.03 A/D 11901 QA790.204I.ENV.A4  1.4 ±0.05 2.1 ± 0.3 0.62 ± 0.02 0.57 ± 0.08  0.4 ± 0.03 11903QA790.204I.ENV.C8 1.6 ± 0.2 0.74 ± 0.06  0.21 ± 0.003 0.54 ± 0.2   0.4 ±0.01 11904 QA790.204I.ENV.E2 1.2 ± 0.3 0.47 ± 0.09  0.4 ± 0.05 0.33 ±0.04 0.61 ± 0.03 A2/D 11905 QG393.60M.ENV.A1 0.41 ± 0.2  1.3 ± 0.1 0.24± 0.02 0.43 ± 0.02   1 ± 0.06 11906 QG393.60M.ENV.B7 0.8 ± 0.3 0.41 ±0.4  0.35 ± 0.01 0.37 ± 0.03 0.43 ± 0.02 A/E 11603 CRF01_AE clone 2691.5 ± 0.3  2 ± 0.2  0.7 ± 0.02 0.77 ± 0.09 0.81 ± 0.2  (potential) AA0583.3 ± 1.2  1 ± 0.2  0.21 ± 0.008 0.83 ± 0.2  0.51 ± 0.07 A/G 11601CRF02_AG clone 263 1.4 ± 0.3 1.5 ± 0.2 0.59 ± 0.09 0.46 ± 0.06 N.D.11602 CRF02_AG clone 266  1 ± 0.2 1.6 ± 0.2 0.68 ± 0.02 0.48 ± 0.03 0.48± 0.07 11605 CRF02_AG clone 278 1.3 ± 0.5 1.1 ± 0.2 0.68 ± 0.02 0.64 ±0.1   0.5 ± 0.03 B B41 0.68 ± 0.1  0.32 ± 0.02 0.28 ± 0.03 0.51 ± 0.030.36 ± 0.04 11578 pWEAUd15.410.5017  3 ± 0.1 0.67 ± 0.1  0.28 ± 0.040.43 ± 0.1   0.5 ± 0.04 11018 QH0692, clone 42 0.52 ± 0.1  1.6 ± 0.20.49 ± 0.05 0.39 ± 0.07 0.35 ± 0.06 11022 PVO, clone 4 1.9 ± 0.1 1.3 ±0.3 0.74 ± 0.07 0.72 ± 0.03  0.5 ± 0.05 11023 TRO, clone 11  1.2 ± 0.05 1.4 ± 0.04 0.51 ± 0.09 0.65 ± 0.1  0.83 ± 0.2  11024 AC10.0, clone 290.32 ± 0.01 0.54 ± 0.1  0.29 ± 0.03  0.4 ± 0.08  0.5 ± 0.02 11035pREJO4541 clone 67 1.6 ± 0.3  1 ± 0.2 0.43 ± 0.03 0.57 ± 0.06 0.74 ±0.1  11036 PRHPA4259 clone 7 1.4 ± 0.2 0.86 ± 0.3  0.32 ± 0.01 0.43 ±0.1  0.57 ± 0.08 11037 PTHRO4156 clone 18  1 ± 0.2 0.82 ± 0.08 0.69 ±0.08 0.75 ± 0.07 0.54 ± 0.05 11038 pCAAN5342 clone A2  0.6 ± 0.07 0.39 ±0.02 0.22 ± 0.02 0.58 ± 0.03  0.6 ± 0.03 11058 SC422661.8 0.33 ± 0.010.54 ± 0.02  0.2 ± 0.01 0.38 ± 0.07 0.53 ± 0.05 C 11306 Du156, clone 122.2 ± 0.5  1.3 ± 0.08 0.43 ± 0.08 0.32 ± 0.03 0.62 ± 0.2  11307 Du172,clone 17 1.9 ± 0.5 0.78 ± 0.1  0.59 ± 0.06 0.87 ± 0.07 N.D. 11308 Du422,clone 1 3.3 ± 0.4 0.81 ± 0.2  0.62 ± 0.06 0.86 ± 0.1  N.D. 11309ZM197M.PB7 2.2 ± 0.5 0.43 ± 0.05  0.3 ± 0.04 0.23 ± 0.02 0.36 ± 0.0411310 ZM214M.PL15 2.7 ± 0.2 1.1 ± 0.1 0.42 ± 0.03 0.26 ± 0.01 N.D. 11311ZM233M.PB6 1.3 ± 0.1 0.91 ± 0.04 0.21 ± 0.02 0.47 ± 0.1  N.D. 11312ZM249M.PL1 3.1 ± 0.5 2.4 ± 0.4  1 ± 0.1 0.41 ± 0.03 0.71 ± 0.07 11313ZM53M.PB12 1.5 ± 0.2 1.6 ± 0.2  0.6 ± 0.04 0.65 ± 0.05 0.85 ± 0.03 11314ZM109F.PB4  2.5 ± 0.06 1.4 ± 0.2 0.75 ± 0.2  0.52 ± 0.04 0.79 ± 0.0511315 1.ZM135M.PL10a 2.7 ± 1.2 0.74 ± 0.09 0.38 ± 0.03 0.25 ± 0.03 0.53± 0.1  11316 CAP45.200.G3 1.2 ± 0.2 0.63 ± 0.05  0.15 ± 0.003 0.27 ±0.06 0.44 ± 0.04 11317 CAP210.2.00.E8 2.8 ± 0.7 0.76 ± 0.05 0.43 ± 0.050.45 ± 0.03 0.69 ± 0.08 11502 HIV-16055-2, clone 3 2.3 ± 0.1 1.2 ± 0.20.86 ± 0.08 0.44 ± 0.1  0.61 ± 0.06 11908 QB099.391M.ENV.B1 1.7 ± 0.40.89 ± 0.3  0.47 ± 0.03 0.27 ± 0.01 N.D. 11909 QB099.391M.ENV.C8 1.8 ±0.5 1.3 ± 0.2 0.49 ± 0.5   0.3 ± 0.02 N.D. D 11911 QA013.70I.ENV.H1 2.6± 0.2 2.2 ± 1.6 0.66 ± 0.04 0.25 ± 0.02 N.D. 11912 QA013.70I.ENV.M12 2.2± 0.3 0.54 ± 0.07  0.3 ± 0.01 0.36 ± 0.04 N.D. 11916 QD435.100M.ENV.B51.6 ± 0.4 1.4 ± 0.3 0.26 ± 0.4  0.41 ± 0.1  N.D. 11918 QD435.100M.ENV.E13.7 ± 0.1 0.52 ± 0.3  0.46 ± 0.09 0.47 ± 0.06 N.D. N.D. Not Determined

TABLE 3 Antiviral activity of NBD compounds in a HIV-1 cell-cell fusionassay, and in assays using HIV-1 reverse transcriptase (RT) andintegrase enzymes. Inhibitors IC₅₀ (μM) Cell-Cell fusion Assay Compound15 9.8 Compound 17 10.8 Compound 19 7.6 NBD-556 6.5 BMS-378806 (control)0.014 HIV-1 Reverse Transcriptase (RT) assay Compound 17 43.4 Compound41 2.56 Compound 90 2.72 NBD-556 >200 Nevirapine (control) 0.20 AZT-TP(control) 0.008 HIV-1 Integrase Assay Compound 17 >100 Compound 41 >100Compound 90 >100 NBD-556 >200 Raltegravir (control) 0.21

TABLE 4 Antiviral activity of the NBD compounds in laboratory- adaptedand primary HIV-1 isolates and toxicity values IC₅₀ (μm) HIV-1 virusSubtype Cell Type Co-receptor NBD-556 NBD-09027 Compound 15 LaboratoryStrains IIIB B MT-2 X4  6.5 ± 0.1 4.7 ± 0.6 3.46 ± 0.2  MN B MT-2 X415.9 ± 1.6  4 ± 0.9 2.1 ± 0.1 SF2 B MT-2 R5X4 ≥118 5.7 ± 0.9 2.6 ± 0.3RF B MT-2 R5X4 18.7 ± 1.3 9.6 ± 0.8 7.3 ± 0.6 BaL B PBMC R5 ≥118 35.8 ±1.2  3.7 ± 0.4 89.6 B PBMC R5X4 4.8 ± 1  6.7 ± 0.3 1.2 ± 0.1 SF162 BPBMC R5 48.9 ± 7.3 12.7 ± 0.7  2.6 ± 0.5 RT-Resistant Isolate AZT-R BMT-2 X4   58 ± 14.3 4.4 ± 1.1  3 ± 0.1 Protease Resistant IsolateHIV-1_(RF/L-323-12-3) B MT-2 X4  >59 14.7 ± 2.3  6.7 ± 0.3 FusionResistant Isolate pNL4-3 gp41_((36G) V38E, N42S) B MT-2 X4  11 ± 0.9 5.8± 0.3 2.2 ± 0.1 Primary isolates 92US657 B PBMC R5   48 ± 1.65 8.6 ± 0.93.3 ± 0.9 93IN101 C PBMC R5 — >87 2.9 ± 0.1 93MW959 C PBMC R5 57.2 ± 8.7  >43.5 2.3 ± 0.5 93TH060 E PBMC R5  >45 7.2 ± 0.6 5.5 ± 1.2 RU570 GPBMC R5 19.5 ± 2.3 8.5 ± 0.8 2.5 ± 0.6 BCF02 (Group 0) PBMC R5 — ~87 9.6 ± 1.1 NBD-556 NBD-09027 Compound 15 MT-2 CC₅₀ (μM) >280 >108 ~28PBMC CC₅₀ (μM) >280 >160 ~36 >indicating that 50% toxicity or activityrespect to the untreated control at this dose was not reached

The foregoing description details specific methods and compositions thatcan be employed to make and use the compounds described herein, andrepresents the best mode contemplated. However, it is apparent for oneof ordinary skill in the art that further compounds with the desiredpharmacological properties can be prepared in an analogous manner, andthat the disclosed compounds can also be obtained from differentstarting compounds via different chemical reactions. Similarly,different pharmaceutical compositions may be prepared and used withsubstantially the same result. Thus, however detailed the foregoing mayappear in text, it should not be construed as limiting the scope of theclaims.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the present invention. Othermodifications that may be employed are within the scope of theinvention. Thus, by way of example, but not of limitation, alternativeconfigurations of the present invention may be utilized in accordancewith the teachings herein. Accordingly, the present invention is notlimited to that precisely as shown and described.

What is claimed is:
 1. A compound represented by a formula A:

or a pharmaceutically acceptable salt thereof, wherein Ph is optionallysubstituted phenyl; Py is optionally substituted pyrrolyl; or Ph-Py isoptionally substituted indolyl; R¹ is H or C₁₋₆ hydrocarbyl; A is H,optionally substituted imidazolyl, optionally substituted thiazolyl,optionally substituted pyrrolyl, morpholine-4-carbonyl,((2-(methylsulfonamido)ethyl)carbamoyl), optionally substitutedpiperazin-1-ylcarbamoyl, optionally substituted morpholinocarbamoyl, or(2-hydroxyethyl)carbamoyl; and B is optionally substituted amino(C₁₋₃alkyl), acetaminomethyl, optionally substituted piperidinyl, optionallysubstituted guanidino, optionally substituted guanidino(C₁₋₃ alkyl),optionally substituted phenyl, optionally substituted furanyl,optionally substituted triazolyl, optionally substituted pyrazolyl, oroptionally substituted phenylmethyl; or

is optionally substituted pyrimidinyl.
 2. A compound, furtherrepresented by Formula 1:

or a pharmaceutically acceptable salt thereof, wherein R⁴, and R¹¹ areH; R⁵ is H or a halide; R⁶ is a halide, CH₃, or OCH₃; R⁷ is hydrogen,halide, or OCH₃; R⁹ is hydrogen or OCH₃; R¹³ is CH₂OH; R¹⁴ is H or CH₃;R¹⁵, and R^(15a) are independently H or, C₁₋₆ alkyl; R¹⁶ is H; and Y isC₁₋₃ alkyl.
 3. (canceled)
 4. A compound, further represented by: A)Formula 2:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹³, and R¹⁴ are independently H, a halide, or asubstituent having a molecular weight of 15 Da to 150 Da and consistingof 2 to 5 chemical elements, wherein the chemical elements areindependently C, H, O, N, S, P, F, Cl, Br, or I; R¹¹, R¹⁵, and R^(15a)are independently H, optionally substituted C₁₋₆ alkyl, optionallysubstituted carbamimidoyl, optionally substituted C₁₋₆ aryl, oroptionally substituted C₁₋₆ heteroaryl; R¹⁶ is H or C₁₋₆ hydrocarbyl;and Y is a bond, or C₁₋₃ alkylene; or B) Formula 3:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹³, R¹⁴, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²² areindependently H, a halide, or a substituent having a molecular weight of15 Da to 150 Da and consisting of 2 to 5 chemical elements, wherein thechemical elements are independently C, H, O, N, S, P, F, Cl, Br, or I;R¹¹ is H, optionally substituted C₁₋₆ alkyl, optionally substitutedcarbamimidoyl, optionally substituted C₁₋₆ aryl, or optionallysubstituted C₁₋₆ heteroaryl; and R¹⁶ is H or C₁₋₆ hydrocarbyl; or C)Formula 4:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²³ are independently H, ahalide, or a substituent having a molecular weight of 15 Da to 150 Daand consisting of 2 to 5 chemical elements, wherein the chemicalelements are independently C, H, O, N, S, P, F, Cl, Br, or I; R¹¹ is H,optionally substituted C₁₋₆ alkyl, optionally substituted carbamimidoyl,optionally substituted C₁₋₆ aryl, or optionally substituted C₁₋₆heteroaryl; and R¹⁶ is H or C₁₋₆ hydrocarbyl; D) Formula 5:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, and R²⁸ are independently H, ahalide, or a substituent having a molecular weight of 15 Da to 150 Daand consisting of 2 to 5 chemical elements, wherein the chemicalelements are independently C, H, O, N, S, P, F, Cl, Br, or I; R¹¹ is H,optionally substituted C₁₋₆ alkyl, optionally substituted carbamimidoyl,optionally substituted C₁₋₆ aryl, or optionally substituted C₁₋₆heteroaryl; and R¹⁶ is H or C₁₋₆ hydrocarbyl; or E) Formula 6:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, and R¹⁰ are independently H, a halide, or a substituent having amolecular weight of 15 Da to 150 Da and consisting of 2 to 5 chemicalelements, wherein the chemical elements are independently C, H, O, N, S,P, F, Cl, Br, or I; R¹¹ is H, optionally substituted C₁₋₆ alkyl,optionally substituted carbamimidoyl, optionally substituted C₁₋₆ aryl,or optionally substituted C₁₋₆ heteroaryl; and R¹⁶ is H or C₁₋₆hydrocarbyl; or F) Formula 7:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, and R¹⁰ are independently H, a halide, or a substituent having amolecular weight of 15 Da to 150 Da and consisting of 2 to 5 chemicalelements, wherein the chemical elements are independently C, H, O, N, S,P, F, Cl, Br, or I; R¹¹ is H, optionally substituted C₁₋₆ alkyl,optionally substituted carbamimidoyl, optionally substituted C₁₋₆ aryl,or optionally substituted C₁₋₆ heteroaryl; and R¹⁶ is H or C₁₋₆hydrocarbyl; or G) Formula 8:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R²³, and R²⁶ are independently H, a halide, or asubstituent having a molecular weight of 15 Da to 150 Da and consistingof 2 to 5 chemical elements, wherein the chemical elements areindependently C, H, O, N, S, P, F, Cl, Br, or I; R¹¹ is H, optionallysubstituted C₁₋₆ alkyl, optionally substituted carbamimidoyl, optionallysubstituted C₁₋₆ aryl, or optionally substituted C₁₋₆ heteroaryl; andR¹⁶ is H or C₁₋₆ hydrocarbyl; or H) Formula 9:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, and R²³ are independently H, a halide, or a substituenthaving a molecular weight of 15 Da to 150 Da and consisting of 2 to 5chemical elements, wherein the chemical elements are independently C, H,O, N, S, P, F, Cl, Br, or I; R¹¹ is H, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆ heteroalkyl, optionally substitutedC₁₋₆ aryl, or optionally substituted C₁₋₆ heteroaryl; and R¹⁶ is H orC₁₋₆ hydrocarbyl; or I) Formula 10:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, and R²³ are independently H, a halide, or a substituenthaving a molecular weight of 15 Da to 150 Da and consisting of 2 to 5chemical elements, wherein the chemical elements are independently C, H,O, N, S, P, F, Cl, Br, or I; R¹¹ is H, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆ heteroalkyl, optionally substitutedC₁₋₆ aryl, or optionally substituted C₁₋₆ heteroaryl; and R¹⁶ is H orC₁₋₆ hydrocarbyl; or J) Formula 11:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, and R¹⁰ are independently H, a halide, or a substituent having amolecular weight of 15 Da to 150 Da and consisting of 2 to 5 chemicalelements, wherein the chemical elements are independently C, H, O, N, S,P, F, Cl, Br, or I; wherein R¹¹ is H, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₁₋₆aryl, or optionally substituted C₁₋₆ heteroaryl; and R¹⁶ is H or C₁₋₆hydrocarbyl; or K) Formula 12:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, and R¹⁰ are independently H, a halide, or a substituent having amolecular weight of 15 Da to 150 Da and consisting of 2 to 5 chemicalelements, wherein the chemical elements are independently C, H, O, N, S,P, F, Cl, Br, or I; R¹¹ is H, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₁₋₆aryl, or optionally substituted C₁₋₆ heteroaryl; and R¹⁶ is H or C₁₋₆hydrocarbyl; or L) Formula 13:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, and R¹⁰ are independently H, a halide, or a substituent having amolecular weight of 15 Da to 150 Da and consisting of 2 to 5 chemicalelements, wherein the chemical elements are independently C, H, O, N, S,P, F, Cl, Br, or I; R¹¹ is H, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₁₋₆aryl, or optionally substituted C₁₋₆ heteroaryl; and R¹⁶ is H or C₁₋₆hydrocarbyl.
 5. (canceled)
 6. (canceled)
 7. (canceled)
 8. (canceled) 9.(canceled)
 10. (canceled)
 11. (canceled)
 12. (canceled)
 13. (canceled)14. (canceled)
 15. (canceled)
 16. (canceled)
 17. (canceled) 18.(canceled)
 19. (canceled)
 20. (canceled)
 21. (canceled)
 22. (canceled)23. (canceled)
 24. (canceled)
 25. (canceled)
 26. (canceled)
 27. Thecompound of claim 1, further represented by one of the followingformulas: i)

pharmaceutically acceptable salt thereof; ii)

or a pharmaceutically acceptable salt thereof; iii)

or a pharmaceutically acceptable salt thereof; iv)

or a pharmaceutically acceptable salt thereof; v)

or a pharmaceutically acceptable salt thereof; vi)

or

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof; viii)

or a pharmaceutically acceptable salt thereof; x)

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof; xi)

or

or a pharmaceutically acceptable salt thereof; xii)

or a pharmaceutically acceptable salt thereof; or xiii)

or a pharmaceutically acceptable salt thereof.
 28. (canceled) 29.(canceled)
 30. (canceled)
 31. The compound of claim 2, having thestructure of any one of compounds 99-130.
 32. A composition comprising acompound according to claim
 2. 33. The composition of claim 32, whereinthe composition is a pharmaceutical composition and further comprises atleast one pharmaceutically acceptable carrier.
 34. A method ofinhibiting HIV comprising administering a compound according to claim 2,to a human being infected with HIV.
 35. A method of treating HIVinfection comprising administering a compound according to claim 2, to ahuman being infected with HIV.
 36. The compound of claim 2, wherein R⁵is F.
 37. The compound of claim 2, wherein R⁶ is Cl.
 38. The compound ofclaim 2, wherein R¹⁴ is CH₃.